Heart Disease and Mortality Subclinical

Subclinical Hypothyroidism and the Risk of Coronary Heart Disease and Mortality Nicolas Rodondi; Wendy P. J. den Elzen; Douglas C. Bauer; et al. Online article and related content current as of September 21, 2010.

JAMA. 2010;304(12):1365-1374 (doi:10.1001/jama.2010.1361) http://jama.ama-assn.org/cgi/content/full/304/12/1365

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REVIEW

CLINICIAN’S CORNER

Subclinical Hypothyroidism and the Risk of Coronary Heart Disease and Mortality Nicolas Rodondi, MD, MAS Wendy P. J. den Elzen, MSc Douglas C. Bauer, MD Anne R. Cappola, MD, ScM Salman Razvi, MD, FRCP John P. Walsh, MBBS, FRACP, PhD Bjørn O. A˚svold, MD, PhD Giorgio Iervasi, MD Misa Imaizumi, MD, PhD Tinh-Hai Collet, MD Alexandra Bremner, PhD Patrick Maisonneuve, Ing Jose´ A. Sgarbi, MD Kay-Tee Khaw, MD Mark P. J. Vanderpump, MD, FRCP Anne B. Newman, MD, MPH Jacques Cornuz, MD, MPH Jayne A. Franklyn, MD, PhD, FRCP Rudi G. J. Westendorp, MD, PhD Eric Vittinghoff, PhD Jacobijn Gussekloo, MD, PhD for the Thyroid Studies Collaboration

C

ONTROVERSY PERSISTS ON THE

indications for screening and threshold levels of thyroidstimulating hormone (TSH) for treatment of subclinical hypothyroidism,1-3 defined as elevated serum TSH levels with normal thyroxine (T4) concentrations. Because subclinical hypothyroidism has been associated with hypercholesterolemia4 and atherosclerosis,5 See also Patient Page. CME available online at www.jamaarchivescme.com and questions on p 1392.

Context Data regarding the association between subclinical hypothyroidism and cardiovascular disease outcomes are conflicting among large prospective cohort studies. This might reflect differences in participants’ age, sex, thyroid-stimulating hormone (TSH) levels, or preexisting cardiovascular disease. Objective To assess the risks of coronary heart disease (CHD) and total mortality for adults with subclinical hypothyroidism. Data Sources and Study Selection The databases of MEDLINE and EMBASE (1950 to May 31, 2010) were searched without language restrictions for prospective cohort studies with baseline thyroid function and subsequent CHD events, CHD mortality, and total mortality. The reference lists of retrieved articles also were searched. Data Extraction Individual data on 55 287 participants with 542 494 person-years of follow-up between 1972 and 2007 were supplied from 11 prospective cohorts in the United States, Europe, Australia, Brazil, and Japan. The risk of CHD events was examined in 25 977 participants from 7 cohorts with available data. Euthyroidism was defined as a TSH level of 0.50 to 4.49 mIU/L. Subclinical hypothyroidism was defined as a TSH level of 4.5 to 19.9 mIU/L with normal thyroxine concentrations. Results Among 55 287 adults, 3450 had subclinical hypothyroidism (6.2%) and 51 837 had euthyroidism. During follow-up, 9664 participants died (2168 of CHD), and 4470 participants had CHD events (among 7 studies). The risk of CHD events and CHD mortality increased with higher TSH concentrations. In age- and sex-adjusted analyses, the hazard ratio (HR) for CHD events was 1.00 (95% confidence interval [CI], 0.861.18) for a TSH level of 4.5 to 6.9 mIU/L (20.3 vs 20.3/1000 person-years for participants with euthyroidism), 1.17 (95% CI, 0.96-1.43) for a TSH level of 7.0 to 9.9 mIU/L (23.8/1000 person-years), and 1.89 (95% CI, 1.28-2.80) for a TSH level of 10 to 19.9 mIU/L (n=70 events/235; 38.4/1000 person-years; P⬍.001 for trend). The corresponding HRs for CHD mortality were 1.09 (95% CI, 0.91-1.30; 5.3 vs 4.9/ 1000 person-years for participants with euthyroidism), 1.42 (95% CI, 1.03-1.95; 6.9/ 1000 person-years), and 1.58 (95% CI, 1.10-2.27, n=28 deaths/333; 7.7/1000 personyears; P=.005 for trend). Total mortality was not increased among participants with subclinical hypothyroidism. Results were similar after further adjustment for traditional cardiovascular risk factors. Risks did not significantly differ by age, sex, or preexisting cardiovascular disease. Conclusions Subclinical hypothyroidism is associated with an increased risk of CHD events and CHD mortality in those with higher TSH levels, particularly in those with a TSH concentration of 10 mIU/L or greater. www.jama.com

JAMA. 2010;304(12):1365-1374

screening and treatment have been advocated to prevent cardiovascular disease.3 However, data on the associations with coronary heart disease (CHD) events and mortality are conflicting among several large prospective cohorts.6-9 Three recent study-level metaanalyses10-12 found modestly increased

©2010 American Medical Association. All rights reserved.

risks for CHD and mortality, but with heterogeneity among individual studies that used different TSH cutoffs, difAuthor Affiliations are listed at the end of this article. Corresponding Author: Nicolas Rodondi, MD, MAS, Department of Ambulatory Care and Community Medicine, University of Lausanne, Bugnon 44, 1011 Lausanne, Switzerland ([email protected]).

(Reprinted) JAMA, September 22/29, 2010—Vol 304, No. 12


1365

SUBCLINICAL HYPOTHYROIDISM AND RISK OF CORONARY HEART DISEASE, MORTALITY

ferent confounding factors for adjustment, and varying CHD definitions.10 Part of the heterogeneity might also be related to differences in participants’ age, sex, or severity of subclinical hypothyroidism (as measured by TSH level).4 One cohort study suggested particularly high risk in participants with subclinical hypothyroidism and preexisting cardiovascular disease.8 Analysis of individual participant data from large cohort studies may reconcile these conflicting data and define the influence of age, TSH levels, and preexisting cardiovascular disease. Individual participant data analysis is considered the best way for synthesizing evidence across several studies because it is not subject to potential bias from study-level meta-analyses (ecological fallacy)13 and allows performance of time-to-event analyses.14 To clarify the cardiovascular risk of subclinical hypothyroidism, we formed the Thyroid Studies Collaboration and conducted an individual participant data analysis of subclinical hypothyroidism and CHD outcomes. METHODS Identification of potential studies was based on protocols developed for our study-level meta-analysis of prospective cohort studies.10 Briefly, we conducted a systematic literature search of articles in all languages on the association between subclinical thyroid dysfunction and CHD or mortality (cardiovascular and total) published from 1950 to May 31, 2010, in the MEDLINE and EMBASE databases and searched bibliographies of key articles (details are available in the eMethods at http://www .jama.com). To maximize the quality and comparability of the studies, we formulated general inclusion criteria a priori. We included only full-text, published longitudinal cohort studies that (1) measured thyroid function with both serum TSH level and thyroxine (T4) level at baseline in adults, (2) followed up participants systematically over time, (3) assessed CHD events and/or mortality, and (4) had a comparison group with euthyroidism. We

excluded studies that only examined persons taking antithyroid medications, thyroxine replacement or amiodarone, or with overt hypothyroidism (defined as low T4 and elevated TSH concentrations). Possible studies for inclusion were independently assessed for suitability by 2 of the authors (N.R., J.G.) and any disagreement was resolved by discussion with a third author (D.C.B). The agreement between the 2 reviewers was 99.9% for the first screen (titles and abstracts, ␬=0.98) and 100% for the full-text screen (␬=1.00). Investigators from each eligible study were invited to join the Thyroid Studies Collaboration. We collected detailed informationaboutprespecifiedoutcomes and potential confounding variables for each participant. Requested data included individual demographic characteristics, baseline thyroid function (TSH and T4 levels), baseline cardiovascular risk factors (eg, low- and high-density lipoprotein cholesterol level, diabetes, blood pressure, cigarette smoking), prevalent cardiovascular disease, medication use at baseline (thyroid medication, lipid-lowering and antihypertensive drugs), and outcome data. To maximize the comparability of the studies, we used a common definition of subclinical hypothyroidism. Based on expert reviews1,2 and definitions used in the Cardiovascular Health Study,6,15 we defined subclinical hypothyroidism as a serum TSH level of 4.5 mIU/L or greater to less than 20 mIU/L, with a normal T4 concentration;andeuthyroidismwasdefined as a serum TSH level of 0.5 mIU/L or greater and less than 4.5 mIU/L. Because the Whickham Survey used a firstgeneration TSH radioimmunoassay, which gives higher measured TSH values than current assays,16 a TSH range of 6.0 mIU/L or greater to less than 21.5 mIU/L was used for this individual participant data analyses, as in the original and recent analysis of this study.17,18 In thatstudy,aserumTSHlevelof6.0mIU/L corresponded to the 97.5th percentile of the group with negative thyroid antibodies,18 which is close to the modern level of 4.5 mIU/L for the current generation of assays. For T4 level, we used site- and

1366 JAMA, September 22/29, 2010—Vol 304, No. 12 (Reprinted)

method-dependent specific cutoffs (eTable at http://www.jama.com) because T4 measurements show greater intermethod variation than do sensitive TSH assays. The Whickham Survey measured total T4 level.18 Participants with abnormal T4 values, results suggestive of nonthyroidal illness (low TSH and FT4 levels) or low TSH level (⬍0.5 mIU/L) were excluded (n=3023). Some studies had participants with missing T4 values (eTable); we considered participants with a TSH level of 4.5 mIU/L to 19.9 mIU/L and a missing T4 level as having subclinical hypothyroidism because most adults with this degree of TSH elevation have subclinical and not overt hypothyroidism. 1 9 We performed a sensitivity analysis excluding those with a missing T4 level. Outcome measures were CHD events, CHD mortality, and total mortality. To limit outcome heterogeneity observed with previous study-level meta-analyses,10-12 we used more homogeneous outcome definitions. Similar to the current Framingham risk score,20 we limited cardiovascular mortality to CHD mortality or sudden death (eTable). A CHD event was defined as nonfatal myocardial infarction or CHD death (equivalent to hard events in the Framingham risk score20) and hospitalization for angina or coronary revascularization (coronary artery bypass grafting or angioplasty). 6 We performed a sensitivity analysis with hard events only. Using previously described criteria10 and new information from study authors, we systematically evaluated the following key indicators of study quality13: methods of outcome adjudication and ascertainment, accounting for confounders, and completeness of follow-up ascertainment. Two reviewers (N.R., J.G.) rated all studies for quality. We used separate Cox proportional hazard models to assess the associations of subclinical hypothyroidism with CHD events and mortality for each cohort (SAS version 9.2, SAS Institute Inc, Cary, North Carolina). Pooled estimates for each outcome were calculated using random-effects models, based




on the variance model according to DerSimonian and Laird,21 as recommended14,22 and published in recent 2-stage individual participant data analyses.23 Results were summarized using forest plots (Review Manager version 5.0.24, Nordic Cochrane Centre, Copenhagen, Denmark). The research authors of 1 study with 14 CHD outcomes 5,10 declined to participate; as recommended,24 we included the published summary estimate from that study in the random-effects models in a sensitivity analysis. To assess heterogeneity across studies, we used the I2 statistic, which describes the total variation across studies attributable to heterogeneity rather than chance (I2⬎50% indicating at least moderate statistical heterogeneity).25 Primary analyses were adjusted for age and sex, and then for traditional cardiovascular risk factors (systolic blood pressure, smoking, total cholesterol, diabetes) that were available in all cohorts (except for the Birmingham Study,26 which was excluded from this analysis). We considered the age- and sex-adjusted model as the primary analysis because some traditional risk factors are potential mediators of the relationship between subclinical hypothyroidism and CHD.4 To explore sources of heterogeneity, we performed several predefined subgroup and sensitivity analyses. We conducted stratified analyses by age, sex, race, TSH concentrations, and preexisting cardiovascular disease. Based on expert reviews1,2 and previous studies,7,15 subclinical hypothyroidism was stratified according to the following TSH concentration categories: 4.5-6.9 mIU/L (mild elevation), 7.0-9.9 mIU/L (moderate elevation), and 10.0-19.9 mIU/L (marked elevation). In the study-specific analyses stratified by age or TSH level, some strata had participants without either CHD deaths or CHD events (for 1 study27). For these study-specific analyses, we used penalized likelihood methods28 to obtain hazard ratios (HRs) and confidence intervals (CIs). As done in previous studies,7,27,29 after including all participants in the primary analyses, we performed sensitivity analyses exclud-

ing participants who had thyroid hormone use at baseline and during followup. To calculate age- and sex-adjusted rates per 1000 person-years, we first fit Poisson models30 to the pooled data, then standardized the fitted rate in the euthyroidism group to the overall age and sex distribution of the pooled sample. Finally, to obtain rates in the TSH groups consistent with the meta-analytic results, we multiplied the standardized rates in the euthyroidism group by the summary meta-analytic HRs. We checked the proportional hazard assumption using graphical methods and Schoenfeld tests (all P⬎.05). We used the Egger test31 and age- and sex-adjusted funnel plots to assess for publication bias. RESULTS Among 4440 reports identified, 12 prospective studies met eligibility criteria (eFigure at http://www.jama.com) and 11 prospective cohorts in the United States, Europe, Australia, Brazil, and Japan agreed to provide individual participant data (TABLE 1). The final sample included 55 287 adults comprising 3450 with subclinical hypothyroidism (6.2%) and 51 837 with euthyroidism. Zero to 8.3% of participants reported thyroid hormone use at baseline (all excluded in 5 studies) and 0% to 12.6% reported thyroid hormone use during follow-up. The median follow-up ranged from 2.5 to 20 years, with total follow-up of 542 494 person-years. All 11 cohort studies reported total and CHD deaths, and 7 studies also reported CHD events among 25 977 participants. For the quality of individual studies, all studies reported outcome adjudication without knowledge of thyroid status; 4 of 7 studies reporting CHD events used formal adjudication procedures6-8,27; and 4 of 11 studies reporting CHD deaths mainly used death certificates.26,33-35 All studies had 5% or less loss to follow-up. During follow-up, 9664 participants died (2168 of CHD) and 4470 participants had CHD events (among 7 studies). In age- and sex-adjusted analyses, the overall HR for participants with subclinical hypothyroidism compared with


euthyroidism was 1.18 (95% CI, 0.991.42) for CHD events (24.0 vs 20.3/ 1000 person-years for participants with euthyroidism), 1.14 (95% CI, 0.991.32) for CHD mortality (5.5 vs 4.9/ 1000 person-years), and 1.09 (95% CI, 0.96-1.24) for total mortality (23.1 vs 21.1/1000 person-years; FIGURE 1). We found heterogeneity across studies for CHD events (I2 =59%) and total mortality (I2 =66%), but not for CHD mortality (I2 =0%). We subsequently examined whether heterogeneity was related to differences in risks by degree of subclinical hypothyroidism and age. The risk of CHD events (P⬍.001 for trend) and CHD death (P =.005 for trend) increased with higher TSH level, but not for total mortality (FIGURE 2). In stratified analyses, participants with TSH levels of 10 mIU/L or greater had significantly increased risk of CHD events (HR, 1.89 [95% CI, 1.28-2.80]; n=70 events/235; 38.4 vs 20.3/1000 personyears for participants with euthyroidism) and CHD mortality (HR, 1.58 [95% CI, 1.10-2.27]; n = 28 deaths/ 333; 7.7 vs 4.9/1000 person-years) compared with participants with euthyroidism. The risk for CHD associated with subclinical hypothyroidism appeared to be somewhat higher in younger participants, but the number of outcomes in the younger age group was small, and there was no significant trend in CHD risk across age groups. Otherwise, the risk estimates for CHD events, CHD mortality, and total mortality did not differ significantly according to age, sex, race, or preexisting cardiovascular disease, except an increase in CHD events and CHD mortality among white but not among nonwhite participants with subclinical hypothyroidism (TABLE 2). All results were similar after further adjustment for traditional cardiovascular risk factors. Sensitivity analyses yielded similar results, with increased risks of CHD events and mortality in those with TSH levels of 10 mIU/L or greater (TABLE 3). Risk estimates were slightly higher for those with TSH levels of 10 mIU/L or greater after excluding those who took thyroid medication during follow-up.



1367


COMMENT In this analysis of 55 287 individual participants from 11 prospective cohort studies, subclinical hypothyroidism was associated with an increased risk of CHD events and CHD mortality in those with higher TSH levels. There was a significant trend of increased risk at higher serum TSH concentrations, and the risk of both CHD mortality and CHD events was significantly increased in participants with TSH levels of 10 mIU/L or greater. These associations persisted after adjustment for traditional cardiovascular risk factors, and did not significantly differ by age,

Estimates were lower for subclinical hypothyroidism overall after limiting the analyses to 4 studies with formal adjudication procedures, but slightly higher for those with TSH levels of 10 mIU/L or greater. The effect of increasing TSH level on CHD events did not significantly differ according to age (P=.87 for interaction). We found no evidence of publication bias, either with visual assessment of age- and sex-adjusted funnel plots or with the Egger test for mortality data (P = .39 for CHD mortality and P=.97 for total mortality) and little evidence of publication bias for CHD events (P=.13 for CHD events).

sex, race, or preexisting cardiovascular disease. Compared with participants with euthyroidism, the overall HR for CHD events with subclinical hypothyroidism was 1.18 (95% CI, 0.991.42) and the overall HR for CHD mortality was 1.14 (95% CI, 0.99-1.32). Minimal TSH elevations were not associated with an increased risk of CHD events and CHD mortality. Our results clarify the CHD risk of subgroups of adults with subclinical hypothyroidism, which could not be adequately addressed in previous studylevel meta-analyses10-12 or in single cohort studies performed in more lim-

Table 1. Baseline Characteristics of Individuals in Included Studies (N=55 287) Thyroid Medication Use, No. (%)

No. (%)

Study

Description of Study Sample

No.

Age, Median (Range), y a

Cardiovascular Health Study,6 2006

CDAs with Medicare eligibility in 4 US communities

3003

71 (64-100)

Health, Aging, and Body Composition Study,7 2005

CDAs aged 70-79 y with Medicare eligibility in 2 US communities

2660

74 (69-81)

1098

68 (60-94)

12 617 24 590

Birmingham CDAs aged ⱖ60 y from Study,26 2001 primary care practice in Birmingham, England EPIC-Norfolk Adults aged 45-79 y living Study,32 2010 in Norfolk, England HUNT Study,33 2008

Adults aged ⬎40 y living in Nord-Trøndelag County, Norway

All adults aged 85 y living in Leiden 85-plus Leiden, the Netherlands Study,27 2004 8

Women

Subclinical At During Hypothyroidism Baseline c Follow-up

United States 1803 (60.0) 492 (16.4)

Follow-up b

Start, y

Duration, Median Person(IQR), y Years

0

153 (5.1)

1989-1990

13.9 (8.7-16.4)

36 865

335 (12.6)

222 (8.3)

334 (12.6)

1997

8.3 (7.3-8.4)

19 410

Europe 622 (56.6)

92 (8.4)

0

28 (2.6)

1988

10.2 (5.9-10.6)

9030

58 (39-78)

6828 (54.1)

720 (5.7)

0

NA

1995-1998

55 (41-98)

16 744 (68.1)

814 (3.3)

0

NA

1995-1997

8.3 (7.9-8.9)

200 334

16 (3.3)

1997-1999

5.2 (2.5-8.5)

2624

2000-2006

2.5 (1.6-3.7)

7710

1338 (50.3)

486

85 (NA)

318 (65.4)

35 (7.2)

14 (2.9)

12.7 153 845 (12.0-13.6)

Pisa cohort, 2007

Patients admitted to cardiology department in Pisa, Italy d

2875

63 (19-92)

921 (32.0)

228 (7.9)

12 (0.4)

Whickham Survey,17,18 1996, 2010

Adults living in and near Newcastle upon Tyne, England

2406

46 (18-92)

1284 (53.4)

124 (5.2)

99 (4.1)

73 (3.0)

1972-1974

19 (15-20)

39 084

Busselton Health Study,9 2005

Adults living in Busselton, Western Australia

1984

51 (18-90)

89 (4.5)

15 (0.8)

33 (1.7)

1981

20.0 (19.4-20.0)

35 158

Atomic bomb survivors in Nagasaki Adult Nagasaki, Japan Health Study,34 2004

2591

57 (38-92)

420 (16.2)

33 (1.3)

6 (0.2)

1984-1987

13.1 (12.3-13.7)

31 559

977

56 (30-92)

NA

1999-2000

7.3 (7.0-7.5)

Brazilian Thyroid Adults of Japanese descent Study,35 2010 living in Sa˜o Paulo, Brazil

Australia 973 (49.0) Asia 1586 (61.2)

South America 518 (53.0) 101 (10.3)

0

0

6875

Abbreviations: CDA, community-dwelling adult; IQR, interquartile range (25th-75th percentiles); NA, data not available. a Participants younger than 18 years were not included. b For all cohorts, the maximal follow-up data that were available were used, which might differ from previous reports for some cohorts. c The numbers of participants with thyroid medication use and thyroid-stimulating hormone levels of 10 mIU/L or greater were 12 of 222 in the Health, Aging, and Body Composition Study; 3 of 14 in the Leiden 85-plus Study; 12 of 12 in the Pisa cohort; 2 of 99 in the Whickham Survey; 2 of 15 in the Busselton Health Study; and 2 of 33 in the Nagasaki Adult Health Study. d Excluded patients with acute coronary syndrome or severe illness.

1368 JAMA, September 22/29, 2010—Vol 304, No. 12 (Reprinted)




participant characteristics (eg, age, TSH concentrations) because of potential bias without individual participant data analysis (ecological fallacy),13 and they also were limited by clinical heterogeneity,10,36 with individual studies using varying TSH cutoffs, confounding factors for adjustment, and CHD definitions. Among 11 cohorts, only 2 studies previously reported results stratified

ited age groups or without TSH stratification.6,7,26,27 These results are generally consistent with previous study-level metaanalyses showing modest increased risks of CHD events and cardiovascular mortality associated with subclinical hypothyroidism.10,11 However, these meta-analyses could not accurately explore potential differences related to

by TSH level. One study9 reported an increased risk of CHD events in participants with a TSH level of 10.0 mIU/L or greater (HR, 2.2; 95% CI, 1.2-4.2) and the other study7 reported an increased risk of cardiovascular mortality (HR, 2.26; 95% CI, 0.54-9.45) but not CHD events (HR, 0.96; 95% CI, 0.35-2.61) over 4 years among adults aged 70 to 79 years with TSH levels of

Figure 1. Subclinical Hypothyroidism vs Euthyroidism for Coronary Heart Disease (CHD) Events, CHD Mortality, and Total Mortality a Subclinical Hypothyroidism No. of Events 180

CHD Eventsb Cardiovascular Health Study,6 2006 Health, Aging, and Body Composition Study,7 2005 EPIC-Norfolk Study,32 2010 Leiden 85-plus Study,27 2004

No. of Participants 492

Euthyroidism No. of Events 955

No. of Participants 2511

HR (95% CI) 1.00 (0.85-1.17)

62

335

493

2325

0.89 (0.68-1.16)

17.4

103

720

1575

11 897

1.09 (0.89-1.33)

20.8 4.5

7

35

76

449

1.29 (0.59-2.80)

Pisa cohort,8 2007

20

228

148

2647

1.72 (1.07-2.74)

9.7


27

121

438

2239

1.32 (0.89-1.96)

11.9


31

89

355

1889

1.78 (1.22-2.58)

12.8

430

2020

4040

23 957

1.18 (0.99-1.42)

100.0

Total (I 2 = 59%)

Decreased Risk

Weight, % 22.9

0.2

0.5

Increased Risk

1

2

5

2

5

2

5

HR (95% CI) CHD Mortalityc Cardiovascular Health Study,6 2006

75

491

365

2511

1.09 (0.85-1.40)

Health, Aging, and Body Composition Study,7 2005

19

335

156

2325

0.85 (0.53-1.37)

33.8 9.2

Birmingham Study,26 2001

11

92

113

1006

1.21 (0.64-2.29)

5.2

EPIC-Norfolk Study,32 2010

31

720

422

11 897

1.19 (0.83-1.72)

15.6

HUNT Study,33 2008

24

814

375

23 776

1.09 (0.72-1.65)

12.1

3

35

41

446

0.87 (0.27-2.82)

1.5

Pisa cohort,8 2007

14

228

92

2647

1.91 (1.08-3.36)

6.6


16

124

223

2282

1.08 (0.64-1.81)

7.8


13

89

144

1892

1.67 (0.94-2.97)

6.3

Leiden 85-plus Study,27 2004

Nagasaki Adult Health Study,34 2004 Total (I 2 = 0%)

4

420

27

2171

0.67 (0.23-1.91)

1.9

210

3348

1958

50 953

1.14 (0.99-1.32)

100.0 0.2

0.5

1

HR (95% CI) Total Mortality Cardiovascular Health Study,6 2006 Health, Aging, and Body Composition Study,7 2005

310

492

1514

2511

1.07 (0.95-1.21)

13.8

92

335

699

2325

0.89 (0.72-1.11)

11.0

Birmingham Study,26 2001

32

92

435

1006

0.92 (0.64-1.33)

7.1

EPIC-Norfolk Study,32 2010

108

720

1716

11 897

0.97 (0.80-1.18)

11.6

HUNT Study,33 2008

116

814

2159

23 776

0.99 (0.82-1.19)

11.9

Leiden 85-plus Study,27 2004

26

35

364

451

0.85 (0.57-1.27)

6.4

Pisa cohort,8 2007

39

228

238

2647

2.13 (1.52-3.00)

7.6


49

124

681

2282

0.98 (0.73-1.31)

8.7


36

89

479

1895

1.44 (1.02-2.03)

7.6

Nagasaki Adult Health Study,34 2004

94

420

409

2171

1.04 (0.83-1.31)

10.8

Brazilian Thyroid Study,35 2010

13

101

55

876

1.96 (1.07-3.61)

3.6

915

3450

8749

51 837

1.09 (0.96-1.24)

100.0

Total (I 2 = 66%)

0.2

0.5

1

HR (95% CI) a The sizes of the data markers are proportional to the inverse variance of the hazard ratios (HRs). CI indicates confidence interval; HUNT, Nord-Trøndelag Health

Study; HR, hazard ratio.

b Forty-six participants from the Whickham survey and 3 participants from the Busselton Health Study were not included because follow-up data were only available for death. c Nine participants were excluded from the analysis because of missing cause of death. The Brazilian Thyroid Study was not included in this analysis because of unreliable es-

timates based on the small number of CHD deaths (n=10).




1369


Our individual participant data analysis found that the CHD outcomes in adults with subclinical hypothyroidism did not differ significantly across age groups. For the specific age group of 80 years or older, there was no significant increased risk of total mortality, CHD mortality, or CHD events in contrast to a single previous study that found reduced mortality associated with increas-

10 mIU/L or greater. However, the HR for CHD events increased to 1.28 (95% CI, 0.68-2.39) with extended follow-up to 8 years in the present data. In overall pooled data, we found statistical heterogeneity among individual study findings for CHD events (I2 =59%), but not for CHD death. Part of the heterogeneity might be related to different CHD risks across age, race, and TSH subgroups.

ing TSH concentrations.27,37 Previous study-level meta-analyses have found increased risks of CHD events and cardiovascular mortality associated with subclinical hypothyroidism, particularly in studies with a mean age of younger than 65 years,10,11 but this was not confirmed by our individual participant data analysis. We found some evidence for increased risks of CHD events and mor-

Figure 2. Hazard Ratios (HRs) for Coronary Heart Disease (CHD) Events, CHD Mortality, and Total Mortality According to Elevated Thyroid-Stimulating Hormone (TSH) Categories and Subclinical Hypothyroidism Stratified by Age vs Euthyroidism a CHD Events by TSH Level, mIU/Lb 0.5-4.49

No. of Events 4040

No. of Participants 23 957

HR Ratio (95% CI) 1 [Reference]

4.5-6.9

264

1344

1.00 (0.86-1.18)

7.0-9.9

96

441

1.17 (0.96-1.43)

10-19.9

70

235

1.89 (1.28-2.80)

Decreased Risk

Increased Risk

P